1,2,4-thiadiazoles

ABSTRACT

New 5-sulfinyl- or sulfonyl-1,2,4-thiadiazoles, e.g. those of the formula R H or an aliphatic or araliphatic radical N 1 OR 2 M 1-7 AND SALTS THEREOF ARE ANTIFUNGAL AGENTS.

United States Patent Rosen et al. [45] Se t. 19, 1972 [54]1,2,4-THIADIAZOLES 72 Inventors: Melvin Harris Rosen, Florham 'f' Mazel1 Park, NJ. 07932- Herbert Morton jac'allagher matter Summit J 0790]Attorney-Harry Goldsmith, Joseph G. Kolodny and Mari0A.M0naco I73]Assignee: Ciba-Geigy Corporation 8 CT 57 AB TRA 221 Filed: Sepl.3, 1970l l New S-sulfinylor sulfonyl-l,2,4-thiadiazoles, e.g. [21] APPl- N69,469 those of the formula 52] 05.0. ..260/302 sn,424/21o ii 51 Int.Cl. ..C07d 91/60 cmmmwsmi 58 Field ofSearch ..260l302 SD W 5 ReferencesCited R H or an aliphatic or araliphatic radical n 1 or 2 OTHERPUBLICATIONS m 1-7 and salts thereof are antifungal agents.

Noguchi et aL, Chem. Abstracts, 70:77873q (1969).

6 Claims, No Drawings 1 ,2,4-THIADIAZOLES SUMMARY OF THE INVENTION Thepresent invention concerns and has for its object the provision of newaliphatically substituted S-sulfinylor sulfonyl-l ,2,4-thiadiazoles,particularly those having Formula I in which R, is hydrogen or analiphatic or araliphatic radical, R is an aliphatic hydrocarbon radical,and n is the integer l or 2, or salts thereof, and methods for thepreparation of said compounds; as well as corresponding pharmaceuticalcompositions, their preparation and use. The compounds of the inventionpossess antifungal activity and are useful for this purpose.

DESCRIPTION OF THE PREFERRED EMBODIMENTS An aliphatic radical R, and R,is, for example, a hydrocarbon radical, such as lower alkyl, e.g.,methyl, ethyl nor i-propyl, -butyl, -pentyl, -hexyl or -heptyl. The termlower," referred to above and hereinafter in connection with organicradicals or compounds respectively, defines such with up to seven,preferably up to four, carbon atoms. Said aliphatic radical, Respecially the lower alkyl group, is unsubstituted or substituted,preferably by one to three halo atoms, e.g., flouro, chloro or bromo, orphenyl groups.

The compounds of the invention exhibit valuable pharmacologicalproperties. For example, they show anti-dermatophyte activity, as can bedemonstrated in in vitro or in in vivo tests, using for the latteradvantageously mammals, such as guinea pigs as test animals. The formertests can be performed according to the gradient plate method with fungiselected, for example, from Trichophyton, Microsporum or the pathogenicyeast strains, e.g., T. mentqgrophytes, T. rubrum or T. simiae; M. canisor M. gypseum; or C. albicans, C. parasilo, C. krusei, Histoplasmacapsulatum or Cryptococcus neoformans. The anti-dermatophyte activitycan also be observed in vivo, e.g., according to Molinus, .l. lnvestig.Dermatol; 25, 33 (1955), where guinea pigs are infected on the shavenback with a homogeneous agar suspension of a day old culture of T.mentagrophytes grown on Sabourauds agar. Treatment with about 0.1-2percent medicated solutions or ointments is started after 24 hours andcontinued once daily for 10 days. During this time, portions of hair andskin scales are taken from 5 different sites of the infected area andsubcultured on Mycosel agar plates, which are incubated and examined forgrowth. Thus, for example, 3-n-butyl-5-ethylsulfonyl 1,2,4-thiadiazole,a characteristic compound of the present invention, showed outstandingactivity in vitro against the above-mentioned fungi, and also, when administered as medicated solutions or ointments in the aboveconcentration, especially at about 2 percent, produced a completesterilization of the infected sites on the backs of guinea pigs, asjudged by the inability to isolate the infecting organism from the siteof infection. Accordingly, the compounds of the invention areusehalo-lower alkyl or mono-, dior tri-phenyl-lower alkyl.

R, is lower alkyl and n is 2.

Especially valuable are compounds of the Formula I in which each of R,and R, is lower alkyl, especially methyl, ethyl, nor i-propyl or butyl.

The compounds of in a invention are prepared according to methods inthemselves known. For example, the process for their preparationconsists in converting a compound of formula I! in which X is a groupcapable of being converted into the R,'S(0),,- group, X into said groupand, if desired, converting any resulting compound into another compoundof the invention.

A suitable group X is, for example, the mercapto group R S, which isconverted into the sulfinyl or sulfonyl group R S (O),, by oxidation.Such oxidation is carried out in the manner known per se, advantageouslywith the use of inorganic or organic oxidation agents, such as halogensor their oxidizing salts, e.g., moist chlorine or sodium periodate,heavy metal oxides or salts, e.g., chromium trioxide or potassiumpermanganate, preferably peroxides, such as hydrogen peroxide orpercarboxylic acids, e.g., perbenzoic, mchloroperbenzoic ormono-perphthalic acid. The formation of sulfoxides or sulfones can becontrolled by the application of equivalent amounts of the oxidationagent and/or the reaction conditions, e.g., temperature orconcentration.

Another group X is, for example, a reactively converted sulfino or sulfogroup, such as a halosulfinyl or sulfonyl, e.g., chlorosulfinyl or-sulfonyl group. The corresponding starting material can be reacted withan R -metal compound, such as a lithium, zinc or advantageouslyhalomagnesium compound, to form the desired compounds of Formula I.

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingagents and/or inert atmospheres, at low temperatures, room temperatureor elevated temperatures, at atmospheric or superatmospheric pressure.

The invention further includes any variant of the present process, inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reaction components are used in the form of their salts. Forexample, alcohols, acids, ammonia, primary or secondary amines may beused in the form of their alkali metal salts or basic reactants in theform of their acid addition salts. Mainly,

those starting materials should be used in the reactions of theinvention that lead to the formation of those compounds indicated aboveas being specially valuable.

The starting material used is known or, if new, may be preparedanalogous to the methods used for the known compounds For example, theS-mercapto compounds can be prepared by condensation of 5-halo-3- R,-l,2,4-thiadiazoles with R -mercaptans in the presence of a strong base,such as an alkali metal hydroxide or alkoxide, e.g., sodium or potassiumhydroxide, methoxide, i-propoxide, tert-butoxide, or especially sodiumethoxide. The 5-halo-3-R -l,2,4- thiadiazoles can be prepared, in turn,according to the methods described in Chem. Ber., 90, 182 (1957) and inAdv. in Heterocycl. Chem., 5, l 19 (1965 The reactively convertedS-sulfinic or sulfonic acids can be obtained from correspondingS-mercaptoor S-benzylmercapto compounds, hydrogen peroxide and ahalogen, e.g., chlorine.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions containing an effectiveamount thereof in conjunction or admixture with excipients suitableespecially for topical use. These compositions contain apharmacologically effective amount, for example from about 0.1 percentto about percent, especially from about 0.5 percent to about 5 percent,of the compounds of the invention together with a pharmaceuticalexcipient. A composition for topical use is advantageously an emulsionpreparation, e.g., a cream, ointment or lotion which, apart from theactive ingredient, contains the usual carrier substances for suchpreparations, e.g., water, benzyl alcohol, cetyl alcohol, propyleneglycol, polyethylene glycol, polysorbate, stearic acid, sodium laurylsulfate, glyceryl monostearate, isopropyl myristate sorbitansesquioleate, lanolin, white petrolatum, liquid petrolatum, spermacetior any other suitable carrier material, and, if necessary, auxiliarysubstances, such as activating agents, e.g., N,N-di-loweralkyl-formamides, for example, N,N-dimethylformamide, preserving agents,e.g., phenyl mercuric acetate, as well as stabilizing, wetting,emulsifying and/or coloring agents. The compositions, which may containother pharmacologically active ingredients, particularly otherantimicrobial agents, are prepared according to the standard methodsemployed in the art.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade.

EXAMPLE 1 To the stirred solution of 10 g3-methyl-5-methylmercapto-l,2,4-thiadiazole in 200 ml chloroform areadded 35.4 g 87 percent mwhloroperbenzoic acid in 400 ml chloroform overa halfhour period at 0. The mixture is allowed to warm up to roomtemperature while stirring overnight. It is filtered, the filtratewashed twice with saturated aqueous sodium bicarbonate, dried, filteredand concentrated. The solid formed is recrystallized from ethanol, toyield the 3-methyl-5- methylsulfonyl-3-methyl-1,2,4-thiadiazole of theformula melting at 93-95.

The starting material is prepared as follows: 2.3 g sodium is dissolvedin 200ml ethanol and cooled to lO, whereupon 4.8 g methylmercaptan isadded. The mixture is allowed to warm up to room temperature and 13 g3-methyl-5-chloro-l,2,4-thiadiazole is added in one portion. Yellowsolids are formed and the temperature rises to about 40. The mixture isthen refluxed for 1% hours, allowed to stir overnight and the solidsremoved by filtration. The filtrate is evaporated in vacuo and theresidue distilled in vacuo, to afford the 3methyl-Smethylmercapto-1,2,4-thiadiazole boiling at 5 l/0.35 mml-lg.

EXAMPLE 2 To 240 ml of a 0.06 molar solution of monoperphthalic acid indiethyl ether is added the solution of 7.7 g3ethyl-S-methylmercapto-l,2,4- thiadiazole in ml diethyl ether over a 5minute period at lO". The mixture is allowed to warm up to roomtemperature while stirring overnight. It is filtered, the filtratewashed twice with saturated aqueous sodium bicarbonate, dried, filteredand concentrated. The residual oil is distilled in vacuo, to afford the3-ethyl-5- methylsulfonyl-l ,2,4-thiadiazole of the formula boiling at llO/0.05 mm Hg.

In an analogous manner to the above, there is also obtained the3-ethyl-5-ethylsulfonyll ,2,4-thiadiazole, b.p. l30-l36/0.l mm Hg.

EXAMPLE 3 To the stirred solution of 7 g3-n-butyl-5-methylmercapto-l',2,4-thiadiazole in 235 ml chloroform areadded 18.2 g 87 percent m-chloroperbenzoic acid in 295 ml chloroformover a half-hour period and maintaining the temperature of the mixturebelow 0. The mixture is allowed to warm up to room temperature whilestirring overnight and worked up in like manner as in Example 1.Following concentration, the residual oil is fractionally distilled invacuo and the fraction boiling at l29-l 34/0.06 mm Hg is collected,yielding the 3n-butyl5-methylsulfonyl-l,2,4-thiadiazole of the formulaIn like manner, treatment of 5 g3-n-butyl-5-ethylmercapto-l,2,4-thiadiazole with 12.2 g 87 percentmchloroperbenzoic acid affords the3-n-butyl-5-ethylsulfonyl-l,2,4-thiadiazole boiling at l52-l56/0.05 mmHg.

EXAMPLE 4 To the stirred solution of 3.7 g 3-trichloromethyl-5-methylmercapto-l,2,4-thiadiazole in 100 ml chloroform are added 9.l g 85percent m-chloroperbenzoic acid in 100 ml chloroform over a half-hourperiod at The mixture is allowed to warm up to room temperature whilestirring overnight and worked up in the usual manner. Followingconcentration, the solid formed is recrystallized from 2-propanol, togive the 3-trichloromethyl-5-methylsulfonyll ,2,4- thiadiazole of theformula 1 i|0c 0 13 N omsml melting at l l l-l 13.

Analogously,-treatment of 3.45 g 3-trichloromethyl-S-ethylmercapto-l,2,4-thiadiazole with 7.95 g 85 percentm-chloroperbenzoic acids affords on recrystallization from 2-propanolthe 3-trichloromethyl-5-ethylsulfonyl-l ,2,4-thiadiazole, m.p. 48-5 l.

EXAMPLE 5 Seven g 3-benzyl-5-methylmercapto-l ,2,4- thiadiazole isdissolved in 200 ml chloroform and the solution treated with 15.7 g 87percent m-chloroperhenzoic acid in 340 ml chloroform added over ahalfhour period at or below 0. The mixture is allowed to warm up to roomtemperature while stirring overnight. Subsequently, it is washed twicewith saturated aqueous sodium bicarbonate, once with water and once withsaturated aqueous brine. The chloroform solution is dried, filtered andconcentrated. The residual solid is recrystallized from ethanol, toyield the 3-benzyl-5- methyl-sulfonyl-l ,2,4-thiadiazole of the formulamelting at 100-l0l.

EXAMPLE 6 100.0 g of an ointment containing 1 percent of the activeingredient are prepared as follows:

Formula l,2,4-thiadiazole 1.0 g Liquid petrolatum 5.0 g White petrolatum94.0 g

Procedure EXAMPLE 7 100.0 g of cream, containing 1 percent of the activeingredient is prepared as follows:

Formula 3-n-butyl-S-ethylsulfonyll ,2,4-thiadiazole Propylene glycolSodium lauryl sulfate Cetyl alcohol Phenyl mercuric acetate Purifiedwater 99 i" o O o O O summons:

Procedure The phenylmercuric acetate is dissolved in 65 ml of water atsubsequently the sodium lauryl sulfate is added and the temperature isreduced to 70. The cetyl alcohol is melted at 70 and added to theaqueous solution while vigorously agitating. Stirring is continued whilecooling the mixture to 45.

The thiadiazole is dispersed in the propylene glycol at 45 and added tothe above emulsion while agitating. Sufficient water is added to bringthe weight to 100 g, and mixing is continued while the product cools toroom temperature. The cream is passed through a three roller mill untiltotal uniformity is accomplished and is filled into epoxy-lined tubes (5g).

We claim:

1. The 1,2,4-thiadiazole of the formula in which R is hydrogen, loweralkyl, mono-, dior trihalo-lower alkyl or mono-, dior tri-phenyl-loweralkyl, R is lower alkyl and n is the integer l or 2.

2. A compound as claimed in claim 1, in which formula R is hydrogen,lower alkyl, mono-, dior tri-halolower alkyl or mono-, diortri-phenyl-lower alkyl, R is lower alkyl and n is 2.

3. A compound as claimed in claim 1, in which formula each of R and R islower alkyl.

4. A compound as claimed in claim 1, and being the3-methyl-5-methylsulfonyl-1 ,2,4-thiadiazole.

5. A compound as claimed in claim 1, and being the3-n-butyl-5-methylsulfonyl-l ,2,4-thiadiazole.

6. A compound as claimed in claim 1, and being the3-n-butyl-5-ethylsulfonyl-l ,2,4-thiadiazole.

mg UNTTED STATES PATENT OFFICE CERTIFICATE OF CORRECTIQN DatedSeptember'l9, 1972 3,69'2J9M v Inventm-(S) MELVIN HARRIS ROSEN ET AL Itis certified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Patent No.

Col. 6, formula. opposite line 35 should read N R S 0 II II 2 )IT' s)Signed and sealed this 7th day of May 1.97M.

EDWARD l-'I.FLETCHER,JH. Attesting Officer Commissioner of Patents

2. A compound as claimed in claim 1, in which formula R1 is hydrogen,lower alkyl, mono-, di- or tri-halo-lower alkyl or mono-, di- ortri-phenyl-lower alkyl, R2 is lower alkyl and n is
 2. 3. A compound asclaimed in claim 1, in which formula each of R1 and R2 is lower alkyl.4. A compound as claimed in claim 1, and being the3-methyl-5-methylsulfonyl-1,2,4-thiadiazole.
 5. A compound as claimed inclaim 1, and being the 3-n-butyl-5-methylsulfonyl-1,2,4-thiadiazole. 6.A compound as claimed in claim 1, and being the3-n-butyl-5-ethylsulfonyl-1,2,4-thiadiazole.